University of Pennsylvania Perelman School of Medicine Philadelphia PA USA.
Heart, Vascular, and Thoracic Institute Cleveland Clinic Cleveland OH USA.
J Am Heart Assoc. 2024 Sep 3;13(17):e033767. doi: 10.1161/JAHA.124.033767. Epub 2024 Aug 29.
Mavacamten is the first and only cardiac myosin inhibitor approved in 5 continents for the treatment of adults with symptomatic New York Heart Association class II and III obstructive hypertrophic cardiomyopathy. An evidence-based rationale was used to develop individualized mavacamten dosing, guided by commonly used clinical parameters. Echocardiography is recommended as part of routine clinical assessment of patients with hypertrophic cardiomyopathy, and left ventricular (LV) outflow tract gradient and LV ejection fraction are parameters that can be readily assessed and monitored by echocardiography. Therefore, an echocardiography-based, clinically guided dose-titration strategy was developed to optimize patient benefit from mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy while minimizing the risk of LV ejection fraction reduction. Results from clinical trials paired with extensive modeling and simulation analyses support a dose-titration and monitoring strategy based on serial echocardiographic measures of Valsalva LV outflow tract gradient and LV ejection fraction. This dosing approach allows for the identification of the lowest individualized mavacamten dose and exposure required to provide improvements in LV outflow tract obstruction, functional capacity, and symptoms. Mavacamten is primarily metabolized by CYP2C19 (cytochrome P450 2C19), and CYP2C19 metabolizer phenotype has an effect on mavacamten exposure. Therefore, this approach has also been demonstrated to provide a favorable safety profile irrespective of patients' CYP2C19 metabolizer status. The dose-titration strategy includes additional considerations for the potential onset of systolic dysfunction in the context of intercurrent illness, and for the potential of drug-drug interactions with inhibitors and substrates of cytochrome P450 enzymes. This posology is reflected in the mavacamten US prescribing information.
马卡塞坦是首个也是唯一一个在五大洲获批用于治疗有症状的纽约心脏协会（NYHA）Ⅱ级和Ⅲ级梗阻性肥厚型心肌病成人患者的心肌肌球蛋白抑制剂。在开发个体化马卡塞坦剂量时，使用了循证医学原理，并以常用的临床参数为指导。超声心动图被推荐作为肥厚型心肌病患者常规临床评估的一部分，左心室（LV）流出道梯度和 LV 射血分数是可以通过超声心动图进行评估和监测的参数。因此，制定了一种基于超声心动图的、临床指导的剂量滴定策略，以优化马卡塞坦治疗有症状梗阻性肥厚型心肌病患者的获益，同时将 LV 射血分数降低的风险降至最低。临床试验结果与广泛的建模和模拟分析相结合，支持一种基于连续超声心动图测量 Valsalva 左心室流出道梯度和 LV 射血分数的剂量滴定和监测策略。这种给药方法可以确定提供 LV 流出道梗阻、功能能力和症状改善所需的最低个体化马卡塞坦剂量和暴露量。马卡塞坦主要由 CYP2C19（细胞色素 P450 2C19）代谢，CYP2C19 代谢表型对马卡塞坦的暴露量有影响。因此，无论患者 CYP2C19 代谢表型如何，这种方法也已被证明具有良好的安全性。该剂量滴定策略还考虑了潜在的因并发疾病而导致的收缩功能障碍，以及与细胞色素 P450 酶抑制剂和底物的药物相互作用的可能性。这种给药方案反映在马卡塞坦的美国处方信息中。
